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| | ==Structure of beta-secretase complexed with inhibitor== | | ==Structure of beta-secretase complexed with inhibitor== |
| - | <StructureSection load='4gid' size='340' side='right' caption='[[4gid]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4gid' size='340' side='right'caption='[[4gid]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gid]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GID OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GID FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gid]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GID OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GID FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0GH:N-[(2S)-1-({(2S,3R)-3-HYDROXY-1-[(2-METHYLPROPYL)AMINO]-1-OXOBUTAN-2-YL}AMINO)-3-PHENYLPROPAN-2-YL]-5-[METHYL(METHYLSULFONYL)AMINO]-N-[(1R)-1-PHENYLETHYL]BENZENE-1,3-DICARBOXAMIDE'>0GH</scene>, <scene name='pdbligand=LPD:L-PROLINAMIDE'>LPD</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0GH:N-[(2S)-1-({(2S,3R)-3-HYDROXY-1-[(2-METHYLPROPYL)AMINO]-1-OXOBUTAN-2-YL}AMINO)-3-PHENYLPROPAN-2-YL]-5-[METHYL(METHYLSULFONYL)AMINO]-N-[(1R)-1-PHENYLETHYL]BENZENE-1,3-DICARBOXAMIDE'>0GH</scene>, <scene name='pdbligand=LPD:L-PROLINAMIDE'>LPD</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1fkn|1fkn]], [[2g94|2g94]], [[2vkm|2vkm]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gid FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gid OCA], [https://pdbe.org/4gid PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gid RCSB], [https://www.ebi.ac.uk/pdbsum/4gid PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gid ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gid FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gid OCA], [http://pdbe.org/4gid PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gid RCSB], [http://www.ebi.ac.uk/pdbsum/4gid PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gid ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> | + | [https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Beta secretase|Beta secretase]] | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Anderson, D]] | + | [[Category: Anderson D]] |
| - | [[Category: Gavande, N]] | + | [[Category: Gavande N]] |
| - | [[Category: Ghosh, A]] | + | [[Category: Ghosh A]] |
| - | [[Category: Huang, X]] | + | [[Category: Huang X]] |
| - | [[Category: Tang, J]] | + | [[Category: Tang J]] |
| - | [[Category: Terzyan, S]] | + | [[Category: Terzyan S]] |
| - | [[Category: Venkateswara, R K]] | + | [[Category: Venkateswara RK]] |
| - | [[Category: Yadav, N]] | + | [[Category: Yadav N]] |
| - | [[Category: A-beta]]
| + | |
| - | [[Category: Alzheimer]]
| + | |
| - | [[Category: App]]
| + | |
| - | [[Category: Aspartic protease]]
| + | |
| - | [[Category: Bace]]
| + | |
| - | [[Category: Beta secretase]]
| + | |
| - | [[Category: Drug design]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Memapsin]]
| + | |
| - | [[Category: Protease]]
| + | |
| Structural highlights
Function
BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2]
Publication Abstract from PubMed
The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective beta-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
Structure-Based Design of Highly Selective beta-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Crystal Structure.,Ghosh AK, Venkateswara Rao K, Yadav ND, Anderson DD, Gavande N, Huang X, Terzyan S, Tang J J Med Chem. 2012 Sep 6. PMID:22954357[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Ghosh AK, Venkateswara Rao K, Yadav ND, Anderson DD, Gavande N, Huang X, Terzyan S, Tang J. Structure-Based Design of Highly Selective beta-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Crystal Structure. J Med Chem. 2012 Sep 6. PMID:22954357 doi:10.1021/jm3008823
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